Cerebrospinal fluid (CSF) specimens were studied in 30 controls, 15 unmedicated bipolars and 25 lithium-treated bipolars. Further measures of peptides related to pro-opiomelanocortin (POMC) have been done on N-terminal fragment (NTF), adrenocorticotropic hormone (ACTH) and beta-endorphin (BE), to enable a more complete assessment of the "cascade" of substances originating in POMC. Measurements of calcitonin have also been made. No patient-control differences were noted in the POMC related peptides, or the other neuropeptides investigated. Lithium treatment was found to decrease plasma and CSF vasoactive intestinal peptide (VIP) but not the other neuropeptides studied. On the lymphocyte, lithium increases affinity of the VIP receptor for its ligand. Two dimensional electrophoresis has been used to study the spinal fluid proteins from many of these persons. No protein charge abnormalities were associated with bipolar affective disorder. We have now entered 42 offspring of bipolar parents and 15 controls into our high risk study of affective illness. Thirty-three skin biopsies have been done. The theoretical underpinnings of high risk studies and the number and type of subjects to be studied have been analyzed. The experimental antidepressant bupropion has been studied in six patients who had not had good response to other agents. Two patients have responded well.